Suicidal behavior is a complex phenotype that includes both attempted and completed suicide. Family, twin, and adoption studies provide strong evidence for a heritable component to suicidal behavior. This heritability appears to be partly dependent on the presence of psychiatric disorders such as bipolar disorder, depression, and alcoholism. Importantly, the heritability also appears to be partly independent of them. Our ongoing studies on the genetics of suicidal behavior have identified linkage regions on 2p11-12 and 6q25-26 and one genome-wide association signal on 2p25 (p=5.07 X 10-8), findings that may lead to important advances in understanding the biological basis underlying suicidal behavior. However, a fuller picture will only emerge as the interaction of genetic susceptibility variants with other factors, such as personality traits and environmental risk factors, are established. Environmental stressors, such as child abuse and early parental loss, are known to play important roles in triggering suicidal behavior, likely through interaction with genetic vulnerability factors. Recent work showing stress-mediated epigenetic control of BDNF, a gene implicated in suicidal behavior, provides molecular evidence that epigenetic mechanisms can mediate this interaction (Tsankova et al., 2006). These results suggest the possibility that new insights into the etiology and pathophysiology of suicidal behavior can be gleaned from further study of epigenetic modifications in post-mortem brains of suicide completers. The tools to perform large-scale epigenetic studies have only just become available, and our Epigenetics Center at Johns Hopkins has been a leader in the development of such tools, having created the Comprehensive High-throughput Arrays for Relative Methylation (CHARM) method for genome-wide DNA methylation (DNAm) studies (Irizarry et al., 2008). We are now proposing to conduct a genome-wide assessment of DNAm using CHARM and samples from the frontal cortex (BA10) of post-mortem brains taken from mood disorder suicide completers and controls. Promising DNAm regions will then be validated using bisulfite pyrosequencing, and validated candidate genes will be screened for differential expression in suicide completers. To accomplish this, we have assembled an outstanding team of investigators with expertise in epigenetics, genetics, biostatistics, and psychopathology. The identification and characterization of differentially methylated genes and genomic regions in suicidal behavior would a) provide new insights into the biological basis of suicidal behavior; b) provide new therapeutic targets; and c) provide the data needed to generate in vivo models in which to test therapeutic targets. These new insights into suicide pathogenesis might allow for dramatic advances in our ability to reduce the global burden of this devastating phenotype.